Research and development of biopharmaceuticals have progressed in recent years, and there are increasing examples of synthesizing peptides and proteins to analyze structure or function, or employing peptides and proteins as medicines. Peptides and proteins are composed of amino acids, and because in α-amino acids that configure proteins the α carbon atom is an asymmetric atom except when the side chain substituent is a hydrogen atom, enantiomers referred to as D- and L-forms exist. Since peptides and proteins that exist in vivo are configured by L-amino acids, optically active L-amino acids are required as the raw material in order to synthesize peptides and proteins that exist in vivo. Moreover, X-ray crystal structure analysis employing racemic proteins are recently gathering attention in protein structure analysis with expectations to increase the crystallization efficiency of proteins. Here, a racemic protein is a protein that is an equal mixture of a protein consisting of only D-amino acids and a protein consisting of only L-amino acids. Analysis of protein structure is an important knowledge in understanding protein function. Demands to synthesize both D- and L-proteins in order to perform structural analysis by crystallization of such racemic proteins are increasing. In order to manufacture such D- and/or L-proteins and stably supply them, it is necessary to efficiently manufacture large amounts of each of optically active D- and L-amino acids as the raw material. In particular, since D-proteins do not exist in nature and can only be synthesized by chemical synthesis, industrial production of D-amino acids to be used as the raw material is essential.
Moreover, when synthesizing a protein as a large molecule, because the length of a peptide that can be manufactured is restricted in the method of manufacturing a peptide by solid phase synthesis etc., the manufactured peptides must be linked. A method referred to as NCL (Native Chemical Ligation) is employed as the peptide linking method. In NCL, a peptide comprising an amino acid possessing a thiol group in the side chain at the N-terminal is linked with the C-terminal of another peptide by utilizing the reactivity of the thiol group. Accordingly, in NCL, protein synthesis is designed mainly with cysteine, which is an amino acid possessing a thiol group in the side chain, as the linking site. For example, a method of having alanine etc. as the linking site by carrying out the linking reaction with a thiol group and then structurally changing it into other amino acids has also been devised. However, amino acids that can be the linking site are still very limited, and this has been the constraint in protein synthesis.
Accordingly, in the manufacture of a D- or L-protein as a large molecule, optically active D- or L-amino acids having a thiol group introduced into the side chain must be manufactured in order to manufacture an amino acid that may be the linking site for NCL. However, although a method of introducing a thiol group into the side chain with D- or L-amino acids as the raw material and via numerous complex steps so that isomerization does not occur has been attempted as the method of manufacturing such amino acids, it is very difficult to manufacture the amino acid of interest with good yield amount and rate by such a method. Reports related to for example a method of employing an enzyme that has stereoselectivity as the method of manufacturing an optically active amino acid also exist (see Patent Literatures 1 and 2). However, there is no particular description in these regarding for example the manufacture of an amino acid possessing a desired substituent such as a thiol group in the side chain. Moreover, since enzymes have substrate specificity, it cannot be said that such enzymes are also effective for an amino acid derivative possessing a bulky substituent such as a protected thiol group at the β-position. Further, in the manufacture of a D- or L-protein as a large molecule, an optically active β-thioamino acid derivative that may be employed as the linking site for NCL has thus far not been manufactured in an aspect that will enable industrial production of D- or L-proteins.